Published on Web 02/27/2002
Enantioselective Addition of Ketene Silyl Acetals to Nitrones Catalyzed by Chiral Titanium Complexes. Synthesis of Optically Active β-Amino Acids Shun-Ichi Murahashi,* Yasushi Imada, Toru Kawakami, Kazuhito Harada, Yoshiharu Yonemushi, and Naomi Tomita Department of Chemistry, Graduate School of Engineering Science, Osaka UniVersity, 1-3, Machikaneyama, Toyonaka, Osaka 560-8531, Japan, and Department of Chemistry, Faculty of Engineering, Okayama UniVersity of Science, 1-1, Ridaicho, Okayama 700-0005, Japan Received December 2, 2001
The synthesis of enantiomerically pure β-amino acids and their derivatives has attracted increasing attention in view of their pharmacological activities,1 structural properties,2 and usefulness as precursors of biologically active compounds such as β-lactam antibiotics.3 Various methods for diastereoselective synthesis of β-amino acids have been reported;4 however, the number of catalytic and enantioselective methods is small and limited to hydrogenation of aminoacrylates,5 aminohydroxylation of olefins,6 addition of aminonucleophiles to acrylates,7 and Mannich-type reaction of aldimines with silyl enolates.8 We report the first catalytic, enantioselective synthesis of optically active N-hydroxyl-β-amino acid derivatives 3, which are related to natural products of biological significance,9 and β-amino acids 4, from nitrones 1 (eq 1). This is a rare case of a catalytic, enantioselective carbon-carbon bond formation reaction.10
Nitrones 1 have become highly valuable intermediates for the synthesis of nitrogen-containing biologically active compounds, because they are prepared readily by catalytic oxidation of secondary amines with H2O211a-g as well as condensation of carbonyl compounds with N-hydroxylamines,11h which can be obtained by hydrolysis of the corresponding nitrones.12 Diastereoselective additions of chiral enolates to nitrones have been performed with excellent selectivity, giving optically active β-amino acids and their derivatives.12,13 This method is very useful for the synthesis of biologically active compounds, such as β-lactams and indolizidine alkaloids.12,13b Catalytic, enantioselective addition of ketene silyl acetals 2 to nitrones 1 is a very attractive proposition for the synthesis of β-amino acid derivatives 3, and is comparable, or in some cases superior, to the asymmetric Mannich-type addition to imines8 because of the configurational stability of nitrones, ease of handling, and readiness of preparation. Various catalysts were evaluated for the reaction of N-benzylidenebenzylamine N-oxide (5a, R ) Ph), which was prepared by the Na2WO4-catalyzed oxidation of dibenzylamine with H2O2,11a with 1-(tert-butyldimethylsilyloxy)-1-methoxyethene (6) (1.2 equiv) in CH2Cl2 at -78 °C (eq 2). In the absence of a catalyst the reaction did not occur, and only a small amount of methyl 3-(N-tertbutyldimethylsilyloxy-N-benzylamino)-3-phenylpropanoate (7a, R * Address correspondence to this author. E-mail:
[email protected].
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) Ph) was obtained with Ti(Oi-Pr)4 catalyst. However, the adduct 7a was obtained in 85% isolated yield, when the reaction was carried out in the presence of Ti(OPh)4 catalyst. Apparently, the phenoxy ligand is suitable for the carbon-carbon bond formation with an increase in the Lewis acidity of titanium. Next, we examined the enantioselectivity of the reaction of 5a with 6 in the presence of various titanium(IV)-BINOL catalysts 8 (20 mol %) in toluene at -78 °C. The representative results are summarized in Table 1. In the presence of chiral titanium catalyst 8a prepared from Ti(OiPr)4 and (S)-BINOL (1:1),14 the adduct (R)-7a was obtained in 99% yield with 18% ee (entry 1). Additional ligands affect the enantioselectivity of the reaction dramatically.15 The catalysts Ti-(S)BINOL-2ArOH 8b,c and Ti-(S)-BINOL-Ar(OH)2 8d,e were prepared in situ by the reaction of Ti(Oi-Pr)4 with 2 equiv of phenols or 1 equiv of catechols, respectively, in toluene at room temperature in the presence of MS 4A, followed by treatment with 1 equiv of (S)-BINOL. In the presence of the titanium catalyst 8b, the adduct (R)-7a was obtained in 99% yield with 34% ee (entry 2). With use of sterically bulky phenols, such as 1-naphthol (55% ee) (entry 3), 2,6-dimethylphenol (50% ee), and 2-phenylphenol (49% ee), (R)7a was obtained with higher enantioselectivities. Interestingly, the adduct (S)-7a with inverse absolute configuration was obtained when catechols were used as additional ligands. Thus, the reaction in the presence of the titanium catalyst 8d gave the (S)-β-amino acid derivative 7a in 73% ee (entry 4). Furthermore, when 4-tertbutylcatechol was used, the adduct (S)-7a was obtained in 99% yield with 92% ee (entry 5). The cleavage of the nitrogen-oxygen bond of the (S)-7a with Zn/H2SO4 and recrystallization of the oxalic acid salt of the product gave optically pure N-benzyl-β-phenylalanine methyl ester. With use of the (R)-BINOL catalyst, the (R)enantiomer was obtained in pure form. The enantioselective addition of ketene silyl acetal 6 to nitrones 5a-e catalyzed by chiral titanium complex 8e gave β-amino acid derivatives 7a-e in high yields as shown in Table 2. R-2-Naphthyl and R-p-tolyl substituted nitrones 5b,c underwent reaction with 6 smoothly to give the desired adducts with 88% ee each (entries 2 and 3). The β-amino-β-arylpropanoic acid derivatives 7b,c thus obtained can be readily converted into the corresponding esters of β-amino acids upon treatment with Zn/H2SO4 and hydrogenation over palladium on charcoal catalyst. The adduct 7e can be converted to ethyl 3-amino-3-[5-(benzo-1,3-dioxole)]propanoate, which is an important precursor of the aspartic acid 10.1021/ja0176649 CCC: $22.00 © 2002 American Chemical Society
COMMUNICATIONS Table 1. Asymmetric Reactions of Nitrone 5a with Ketene Silyl Acetal 6 in the Presence of Ti-(S)-BINOL-2ArOH (or Ar(OH)2) 8 To Give N-Hydroxyl-β-amino Acid Derivative 7a entry
1 2 3 4 5
ArOH or Ar(OH)2 of 8
none phenol 1-naphthol catechol 4-tert-butylcatechol
8a 8b 8c 8d 8e
yield of 7a/%
ee of 7aa/%
config. of 7a
99 99 99 95 99
18 34 55 73 92
(R) (R) (R) (S) (S)
a Determined by HPLC analysis using CHIRALCEL OD-H after conversion to the corresponding β-amino acid ester with Zn/H2SO4.
Table 2. Asymmetric Reactions of Nitrones 5a-e with Ketene Silyl Acetal 6 in the Presence of Titanium Catalyst 8e To Give 7a-ea entry
1 2 3 4 5
R of 5
phenyl 2-naphthyl p-MeC6H4 3-pyridyl 3,4-(OCH2O)C6H3
5a 5b 5c 5d 5e
yield of 7/%
ee of 7/%
config. of 7
99 94 66 90 74
92a 88b 88a 80c 80a
(S) (-) (-) (+) (S)
a Determined by HPLC analysis using CHIRALCEL OD-H after conversion to the corresponding β-amino acid esters with Zn/H2SO4. b Determined by HPLC analysis using CHIRALPAK AD after conversion to the corresponding β-amino acid ester with Zn/H2SO4. c Determined by HPLC analysis using CHIRALCEL OD-H.
mimetic of the RDG (Arg-Gly-Asp) peptide mimetic fibrinogen receptor antagonist, anti-platelet aggregation agent.16 A variety of cyclic nitrones were found to undergo the chiral titanium catalyzed reaction with 6. The addition of 6 to 6,7dimethoxy-3,4-dihydroisoquinoline N-oxide (9a), derived by the catalytic oxidation of the corresponding 1,2,3,4-tetrahydroisoquinoline, in the presence of the titanium catalyst 8e gave 1,2,3,4tetrahydro-1-isoquinolineacetic acid derivative 10a in 84% yield with 83% ee (eq 3).
Recrystallization of the adduct thus obtained from 2-propanol gave optically pure 10a. Treatment of 10a with Zn/H2SO4 gave methyl 6,7-dimethoxy-1,2,3,4-tetrahydro-1-isoquinolineacetate, which is an important precursor of isoquinoline alkaloids. Similarly, the corresponding adduct 10b was obtained in 88% yield with 90% ee. Optically active N-hydroxyl-β-amino acids or β-amino acids can be prepared in large scale from the corresponding secondary amines by two catalytic processes in combination with the catalytic synthesis of nitrones from secondary amines. The reactions exhibit a positive nonlinear relationship between the enantiomeric purities of the chiral titanium catalyst 8e and the products 7a and 10a, indicating that binaphtholato-bridged dimeric complex seems to be involved as the active species in these reactions. The origin of the reversed sense of stereoinduction using
catechol ligands remains unclear. Experiments are underway to examine the mechanism. Acknowledgment. This work was supported by the Research for the Future program, the Japan Society for the Promotion of Science, and a Grant-in-Aid for Scientific Research, the Ministry of Education, Science, Sports and Culture of Japan. Supporting Information Available: Experimental procedures and spectroscopic data for compounds 7 and 10 (PDF). This material is available free of charge via the Internet at http://pubs.acs.org. References (1) For review: (a) Drey, C. N. C. In Chemistry and Biochemistry of the Amino Acids; Barrett, G. C., Ed.; Chapman and Hall: London, 1985; pp 25-54. (b) Griffith, O. W. Annu. ReV. Biochem. 1986, 55, 855-878. (c) Bewley, C. A.; Faulkner, D. J. Angew. Chem., Int. Ed. Engl. 1998, 37, 2162-2178. (2) (a) Seebach, D.; Matthews, J. L. Chem. Commun. 1997, 2015-2022. (b) Gellman, S. H. Acc. Chem. Res. 1998, 31, 173-180. (3) For review: Berks, A. H. Tetrahedron 1996, 52, 331-375. (4) For review: EnantioselectiVe Synthesis of β-Amino Acids; Juaristi, E., Ed.; Wiley-VCH: New York, 1997. (5) Lubell, W. D.; Kitamura, M.; Noyori, R. Tetrahedron: Asymmetry 1991, 2, 543-554. (6) Li, G.; Chang, H.-T.; Sharpless, K. B. Angew. Chem., Int. Ed. Engl. 1996, 35, 451-453 (7) (a) Sibi, M. P.; Shay, J. J.; Liu, M.; Jasperse, C. P. J. Am. Chem. Soc. 1998, 120, 6615-6616. (b) Myers, J. K.; Jacobsen, E. N. J. Am. Chem. Soc. 1999, 121, 8959-8960. (8) Ishitani, H.; Ueno, M.; Kobayashi, S. J. Am. Chem. Soc. 1997, 119, 71537154. (9) Ottenheijm, H. C. J.; Herscheid, J. D. M. Chem. ReV. 1986, 86, 697707. (10) For review: (a) ComprehensiVe Asymmetric Catalysis; Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.; Springer-Verlag: Berlin, 1999; Vols. 1-3. Enantioselective addition of carbon nucleophiles to nitrones. Et2Zn: (b) Ukaji, Y.; Kenmoku, Y.; Inomata, K. Tetrahedron: Asymmetry 1996, 7, 53-56. RMgX: (c) Merchan, F. L.; Merino, P.; Rojo, I.; Tejero, T.; Dondoni, A. Tetrahedron: Asymmetry 1996, 7, 667-670. Zinc acetylides: (d) Frantz, D. E.; Fassler, R.; Tomooka, C. S.; Carreira, E. M. Acc. Chem. Res. 2000, 33, 373-381. (11) Oxidative transformation of secondary amines to nitrones. Na2WO4 catalyst: (a) Mitsui, H.; Zenki, S.; Shiota, T.; Murahashi, S.-I. J. Chem. Soc., Chem. Commun. 1984, 874-875. (b) Murahashi, S.-I.; Mitsui, H.; Shiota, T.; Tsuda, T.; Watanabe, S. J. Org. Chem. 1990, 55, 1736-1744. (c) Murahashi, S.-I.; Shiota, T.; Imada, Y. Org. Synth. 1991, 70, 265271. SeO2 catalyst: (d) Murahashi, S.-I.; Shiota, T. Tetrahedron Lett. 1987, 28, 2383-2386. Flavin catalyst: (e) Murahashi, S.-I.; Oda, T.; Masui, Y. J. Am. Chem. Soc. 1989, 111, 5002-5003. MeReO3 catalyst: (f) Murray, R. W.; Iyanar, K.; Chen, J.; Wearing, J. T. J. Org. Chem. 1996, 61, 80998102. (g) Goti, A.; Nannelli, L. Tetrahedron Lett. 1996, 37, 6025-6028. Other methods: (h) Torssell, K. B. G. In Nitrile Oxides, Nitrones, and Nitronates in Organic Synthesis; VCH: Weinheim, 1988; pp 75-94. (12) Kawakami, T.; Ohtake, H.; Arakawa, H.; Okachi, T.; Imada, Y.; Murahashi, S.-I. Bull. Chem. Soc. Jpn. 2000, 73, 2423-2444. (13) Additon of chiral ketete silyl acetals to nitrones: (a) Ohtake, H.; Imada, Y.; Murahashi, S.-I. J. Org. Chem., 1999, 64, 3790-3791. Additon of chiral enolates to nitrones via N-acyloxyiminium ions: (b) Kawakami, T.; Ohtake, H.; Arakawa, H.; Okachi, T.; Imada, Y.; Murahashi, S.-I. Org. Lett. 1999, 1, 107-110. (c) Kawakami, T.; Ohtake, H.; Arakawa, H.; Okachi, T.; Imada, Y.; Murahashi, S.-I. Chem. Lett. 1999, 795-796. (14) (a) Keck, G. E.; Tarbet, K. H.; Geraci, L. S. J. Am. Chem. Soc. 1993, 115, 8467-8468. (b) Kitamoto, D.; Imma, H.; Nakai, T. Tetrahedron Lett. 1995, 36, 1861-1864. (c) Matsukawa, S.; Mikami, K. Tetrahedron: Asymmetry 1995, 6, 2571-2574. (15) Kawakami, T.; Harada, K.; Imada, Y.; Murahashi, S.-I. Abstracts of Papers, 69th Annual Meeting of the Chemical Society of Japan, Kyoto, Japan; The Chemical Society of Japan: Tokyo, Japan, 1995; Abstract 2H105. See also the ref 14c. (16) Zablocki, J. A.; Rico, J. G.; Garland, R. B.; Rogers, T. E.; Williams, K.; Schretzman, L. A.; Rao, S. A.; Bovy, P. R.; Tjoeng, F. S.; Lindmark, R. J.; Toth, M. V.; Zupec, M. E.; McMackins, D. E.; Adams, S. P.; Miyano, M.; Markos, C. S.; Milton, M. N.; Paulson, S.; Herin, M.; Jacqmin, P.; Nicholson, N. S.; Panzer-Knodle, S. G.; Haas, N. F.; Page, J. D.; Szalony, J. A.; Taite, B. B.; Salyers, A. K.; King, L. W.; Campion, J. G.; Feigen, L. P. J. Med. Chem. 1995, 38, 2378-2394.
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